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Background: Pulse oximetry is widely used in intensive care and emergency conditions to monitor arterial oxygenation and to guide oxygen therapy. Objective: To study the reliability of pulse oximetry in comparison with CO-oximetry in newborn piglets during cardiopulmonary resuscitation (CPR). Methodology: In a prospective cohort study in 30 healthy newborn piglets, cardiac arrest was induced, and thereafter each piglet received CPR for 20 min. Arterial oxygen saturation was monitored continuously by pulse oximetry (SpO2). Arterial blood was analyzed for functional oxygenation (SaO2) every 2 min. SpO 2 was compared with coinciding SaO2 values and bias considered whenever the difference (SpO 2 – SaO 2 ) was beyond ±5%. Results: Bias values were decreased at the baseline measurements (mean: 2.5 ± 4.6%) with higher precision and accuracy compared with values across the experiment. Two minutes after cardiac arrest, there was a marked decrease in precision and accuracy as well as an increase in bias up to 13 ± 34%, reaching a maximum of 45.6 ± 28.3% after 10 min over a mean SaO 2 range of 29–58%. Conclusion: Pulse oximetry showed increased bias and decreased accuracy and precision during CPR in a model of neonatal cardiac arrest. We recommend further studies to clarify the exact mechanisms of these false readings to improve reliability of pulse oximetry during the marked desaturation and hypoperfusion found during CPR.